Process Validation

Harmonized and Practical Approach

AGENDA
1. Process Validation Regulatory Framework
2. Process Validation Terminology
3. Understanding Variability
4. Process Validation Lifecycle Stages
• Process Design – Stage 1
• Process Qualification – Stage 2.1 and 2.2
• Continued Process Verification – Stage 3
5. Limitations and Challenges
6. Case Study#1
7. Case Study#2
Regulatory Background

Validation – "Act of proving in accordance with GMPs that any procedure, process, equipment,
material, activity or system actually leads to the expected results.
European Commission, 1991
Terminology
Validation
• Treated as general umbrella term
Qualification
• Is the equipment / utility designed to work as intended an
confirmed to function within the ranges intended.
Process validation
• Does the process deliver the intended product to the patient-
also in the future? i.e. an agreed control strategy is established
for the product lifecycle.
Difference in International Terms
US EU
Stage 1 Process Design (Pharmaceutical Development or Process
Design)
Stage 2 Process Qualification (PQ) (Qualification)
Stage 2.1 Qualification of Equipment &Utilities User Requirement Specification (URS)
Design Qualification (DQ)
Factory Acceptance Test (FAT)
Site Acceptance Test (SAT)
Installation Qualification (IQ)
Operational Qualification(OQ)
Performance Qualification(PQ)
Stage 2.2 Process Performance Qualification Process Validation (PV)
(PPQ)
Stage 3 Continued Process Verification (CPV) Ongoing Process Verification (OPV)
Definitions of Process Validation

“The collection and evaluation of data, from the process design

stage through to commercial production, which establishes scientific
evidence that a process is capable of continuously delivering the
finished pharmaceutical product, meeting its predetermined
specifications and quality attributes. “ WHO

“ the documented evidence that the process , operated within

established parameters , can perform effectively and reproducibly to
produce a medical product meeting its predetermined specifications
and quality attributes” EMA (activity definition)
Definitions of Process Validation

“establishing documented evidence which provides a high degree

of assurance that a specific process will consistently produce a
product meeting its pre- determined specifications and quality
characteristics“. FDA (lifecycle definition)

“Process validation represents the means of ensuring and

providing supporting documents specifying their design parameters
by whom they are capable repeatedly and reliably produce a
finished product of the required quality”. ICH
Conceptual shift , Non-descriptive, Process knowledge
Data , data, and data
Regulatory Background

Guideline on process
197 Q8, Q9, Q10 and Q11 201 validation for finished
8 1
products

1970 FDA ICH FDA EMA

S
Introduced validation Process Validation
concept Guidance 201
4

201 201
EMA proces validation TRS 992 annex 3
9 5
guidances appendix 7

ISPE EMA EU WHO

Practical implementation
of lifecycle approach to 201
Annex 15
201
process validation 6 5
FDA PV Guidance
GMP Focus

• Design quality, safety & efficacy into the

product
• Quality cannot be assured merely by
inspection & testing.
• Control each step of a manufacturing process
to assure the finished product meets all quality
attributes
• 3 stages approach
• Understanding variability and impact on
product quality.
EU Guidance –Drug product
Submission Focus

• Lifecycle approach; link development, validation &

process.
• “State of control” for routine commercial manufacture
• PV to confirm control strategy adequate to process
design &product quality
• Validate manufacturing before product is marketed
EU Guidance – Biologics- Drug Substance
Submission Focus

• Process evaluation
⁃ Provie evidence the manufacturing process is
appropriately designed & controlled
• Process Validation
⁃ (As Earlier)
• Process verification:
⁃ Studies to confirm manufacturing process can:
⁃ Perform effectively: meet pre determined acceptance
criteria, on X number of batches
• Note API also covered by:
⁃ ICH Q7 (GMP) Q11(Development & manufacturing of
drug substance, small & large molecule)
EU Guidance – Annex 15: GMP Focus
• Lifecycle – ICH Q8, 9, 10 &11.
• Qualification – URS, DQ, FAT, SAT , IQ, OQ, PQ.
• PV should ensure process consistently produce product quality,
ref quality attributes & process parameters.

EU Guidance – ATMP
• Fragility of the product
• Product lifetime
Process Validation purpose

• Demonstrate homogeneity within a batch and consistency

between batches.
• Process understanding
• Understanding sources of variation
• Understanding the impact of process and material variability
and product quality. Established control strategy to control
variation in a manner commensurate with the risk it represents
to the process and product.
 Traditional Vs New Paradigm
1980s
2011
Development
(Basic)

Pilot Batch
manufacturing
Post approval
changes / Process
change validation - 3
control/ risk batches
analysis

Revalidation
No more completed but on-going
 Process variation and Control

CMA CPP
Facility and
DS equipment
Materials, operating
components conditions

Variable Process Consistent output

inputs
IPC Finished product
QTPP , CQA testing
Process Variation and Control
QTPP:
The quality Target product profile provides an understanding of what will ensure quality
, safety and efficacy of a specific product for the patient
CQA:
A physical , chemical, biological or microbiological property that should be within an
appropriate limit, range , or distribution to ensure the desired product quality
(Finished Product Specification)
CPP:
A process parameter whose variability has an impact on the CQA and therefore
should be monitored or controlled to ensure the process produces the desired
quality
CMA:
A physical , chemical, biological or microbiological property of an input material that
should be within an appropriate limit, range , or distribution to ensure the quality of
output material (Material Specification)
 CQAs
Example of Typical CQAs

Drug Substance Bios DS Solid Oral Parentrals Device

Impurities Protein content Bulk density Appearance Potency
Residual solvents Aggregates Flowability Identity homogeneity
Assay Host cell protein Foreign matter assay Flow properties
LOD Biopotency Blend uniformity Impurity Sieve particle size
Color Endotoxins Blend Potency Sterility Bulk/tap density
Particle size Sterility Final potency Endotoxin Appearance
Solution clarity Peptide map Particle size pH Aerosolizability
Particle morphology Residual DNA Content uniformity Particulate matter Actuation force
Bulk density Acidic species Dissolution Volume Pouch seal integrity
Disintegration O2 in headspace
CPPs
Example of Typical CPPs

Solid Oral Parentrals Bios DS

Impeller speed Stopper material Temperature
Sieve size Order of addition Bed hight
Lubricant- specific surface area Sterilization temperature Dissolved oixygen concentration
Air flow Shelf temperature Culture duration
Particle size distribution Drying time Resin life-time
Blend uniformity Air flow Nutrient concentration
Ribbon uniformity N2 flow rate Timing of glucose feed
Mill speed Holding time Medium hold time before
filtration
Holding time Humidity Inoculum in-vitrocell age
Ejection force Mixing speed Antifoam concentration
Process Variation and Control

CQAs
Control Strategy:
A planned set of controls, derived from current Control
strategy
Process
map
product and process understanding that
ensures process performance and product
quality.
The controls can include parameters and
Operating Process Risk
attributes related to drug substance and drug ranges design
assessme
nt
product materials an components, facility, and
equipment operating conditions, in-process
controls finished product specifications, and
the associated methods and frequency of Scale Process
issues parameter
monitoring an controls (Q10) s (CPPs)

Material
attributes
(CMAs)
Enhanced knowledge and controls
qProvide the highest assurance that all production batches will consistently as
efficacious as the clinical batch(es).
qReduce the risk to safety via the highest assurance of acceptable and
consistent quality of the product and its components.
qMaintain and assure a higher degree of quality of drug products.
ü Quality, safety and efficacy must be designed and built into the product.
ü Quality cannot be inspected or tested into the product.
ü Each critical step of the manufacturing process must be validated.
ü Other steps in the process must be under control.
q Reduced end testing and more flexible process
Strict process
Testing Strict process Testing

Knowledge Knowledge
Knowledge Knowledge
 PV Stages ; Product Life-Cycle Approach
Stage #1; Stage #2; Stage #3;
Process Process Continued Process
Design Qualification Verification
• The • The process • Ongoing
commercial design is assurance is
process is evaluated and gained during
defined based assessed to routine
on knowledge determine if the production that
gained through process is the process
development capable of remains in a
and scale-up reproducible state of control
activities commercial
manufacture

Development Technology Commercial Product discontinuation

transfer manufacturing
Validation in Product Lifecycle –
Diagrammatic (EU&US)
Process design (FDA) Process Qualification Continued (FDA)
Pharmaceutical (FDA) Ongoing (EU)
Development (EU) Process Validation (EU) Process Validation

Develop control 2.1 2.2 3a 3b

strategy based on
product quality Qualification of the PPQ (or PV) Heightened Routine
attributes supporting system sampling and monitoring
testing until program
Demonstrate
variability is
effectiveness of control
understood
strategy in commercial
manufacture Monitor process performance &
variability during product life-
cycle
Legacy Products Typically Enter Lifecycle in Stage 3
 Level of Testing& Monitoring
2.2.
1. Process
PPQ(PV 3. Commercial Manufacturing
design
)
Level of Testing

Post Change
periodic introduced/
review CAPA PAT
signal Implemented

Variability Monitoring
Estimate e
established

Control Strategy is dynamic over the lifecycle QC Testing

Time/Process Knowledge
Process Design Goal and Principles

Process Design Goal Process Design Principles

• To design a process suitable • Patient focused
for routine commercial • Science & risk based
manufacturing that can approach (QbD)
consistently deliver a product
that meets its quality • Knowledge management
attributes. • Cross functional
• Establish a control strategy • Understanding impact of
ensuring the product will meet variability on product quality
the CQA requirements.
PV Stages
Process Design Process Continued Process
Qualification Verification

• Quality by design (QbD) •Premises, utilities and • Enhanced control strategy

• Lab/pilot scale equipment qualification (2A) • Capability assessment
• Quality target product •Determine process • Statistical process control
profile (QTPP) Performance qualification(PPQ)
(2B) • Continued improvement
• Critical quality attributes •Commercial scale batches • Continuous product supply
(CQA)
•Verify critical process
• Design of experiment parameters (CPP) and Normal
(DoE) -Design space – operating ranges (NOR)
critical process •Process capability
parameters (CPP) •Commercial Distribution
• Control strategy

Change control
Knowledge management
Risk Management
Data collection and statistical analysis
Stage #1; Process design
Building and • Representative modules/ simulations
capturing • Design of experiments (or other studies ) to identify multivariate
interaction
process • Risk analyses
knowledge

understanding • Contributed by raw materials, environment,

employees, others
variation • Consider both intra and inter variation

• Reduce and/or adjust variation

PROCESS & Establishing • Establish and document process
a strategy of control procedures
ANALYTICS process • Consider implementation of process
control analytical technology
DEVELOPMENT
QbD Principles for Process Design

Starts with Iterative and As a minimum ranges for

the patient in happens in CPPs must be
mind parallel established and
interactions understood

Product Ranges, Control Continual

QTPP CQAs &Process CPPs &CMAs design Space Strategy improvement
Development

Controls of
The CQAs are Identification of CQAs and how
used measures CPPS and they are
of the QTPP CMA “manufactured ,
CPPs an CMAs
 Stage #1; Process Design
Control strategy
A planned set of controls, derived from current product
CMA and process understanding that assures process CPP
performance and product quality

DS Facility and
Materials, equipment
components Feed forward Feed back operating
Environment conditions

Variable Process Consistent output

inputs
Finished product
IPC testing
QTPP , CQA
Establishing a Design Space
Implementing QRM

Consider risks due to:

• Lack of process understanding
• Lack of control on the relationship between
Process inputs and parameters and product
attributes
• Sampling uncertainty
• Scale differences
• Normal operating variability
• Change in process or measurement
behaviour
Implementing QRM

• Relationship to product quality / patient risk

• Variability range has significant or negligible
effect on critical quality attributes (CQAs)
• variable already monitored and controlled
within a separate system
• In-Process Controls s have special
characteristics

• Review periodically and report.

• Frequency based on capability and volume of
data
• More frequent than annually
Implementing QRM
QRM principles:
• The evaluation of risk to product quality
should be based on scientific knowledge
and ultimately link to the protection of the
patient.

• The level of effort, formality and

documentation of the quality risk
management process should
commensurate with the level of risk
QRM Tools

• Use Fit for the purpose risk assessment tools

• Stage 1, prior to stage 2b, stage 3a,3b
• Failure Mode Effect Analysis (FMEA), Failure Mode Effect
Criticality Analysis (FMECA)
• Fault Tree Analysis (FTA); out put from other hazard analysis
• Preliminary Hazard Analysis (PHA); highly dependant on
Subject Matter Expert inputs.
• Hazard analysis and critical control points, (HACCP);
understanding of process and controls.
• Risk ranking and Filtering (RRF).
• Justify your methodology ; data-driven
Identification of Criticality CMA/CPPs
Process Design Tools
Process Design Tools

Operating
Ranges
Specifications and Acceptance Criteria

Specification:
is a list of tests, reference to analytical Marketing
procedures, and acceptance criteria to which an authorization
Active Pharmaceutical Ingredient (API) or limits
Finished Pharmaceutical Product (FPP) should
conform. Batch release
Acceptance criteria: limits
is conditions (numerical limits, ranges or other
criteria), that a product must satisfy to be
accepted Validation
These criteria define the boundaries and limits
parameters.
Control Strategy

Ready for stage 2?

Stage #2; Process Qualification
2.1; Design of facility and 2.2; Process performance
qualification of utilities and
equipment qualification (PPQ)

• Construction material, operating • Combine the qualified facility,

principles, and performance utilities, and equipment (and
characteristics are appropriate trained personnel) with the
• Systems and equipment are commercial manufacturing
built and installed per design process , control procedures
specifications and operate per and components to produce
process requirements across commercial batches
operating ranges • Confirms process design and
demonstrates commercial
process performs as expected
 Stage #2.1; Qualification/ Verification
• Based on Critical quality attributes (CQAs) , critical
process parameters (CPPs), and regulatory requirement
• Quality Risk Management (QRM) principles
• Document
• Team approach
• Assess variability
Design COMISSIONI
User Specifications/F Factory NG/ Site
Requirement unctional Design Acceptance
Specification Design Qualification Test Acceptance
specifications Test

Operation Installation
Qualification Qualification
Stage #2.1; Qualification/ Verification
• Review established equipment qualification ranges

• Assess impact of product and process on facilities, utilities and

systems
• Technology transfer considerations
Stage #2.2;
Process Performance Qualification (PPQ)
§ Confirms the designed process is capable, reproducible and in state of
control within commercial manufacturing conditions .
§ This stage should provide scientific evidence assures that process is
capable of consistently delivering quality product and demonstrate that
process works as intended
§ Successful completion of this stage is necessary before commercial
distribution.
§ Batches manufactured during this stage may be released for commercial
distribution according to level of assurance/ confidence gained.
§ Heightened sampling/testing plans
Number of PPQ batches ??

§ Guidance does not specify how many batches to include in stage

#2 studies
§ Three is not a magic number , should be science and risk- based
according to the overall product/ process performance.
§ Firm must determine and justify PPQ (not one size fits all)
§ Data driven
§ Bracketing, matrix, and/or family could be used when justified.
§ Justify the number of batches and the sample size
Sampling plans
§Designed based on sources and patterns of variability.
§Used to conclude process capability, controllability and reproducibility,
§ Must be large enough to conclude statistical capability
§ Influenced by ;
§ Process knowledge
§ Similar Product and process performance
§ Statistical methods and metrics
Sampling Method & size
Proper sampling method: Random , systematic, ..etc
Allows application of statistical sampling theory to results to generalize and
test hypotheses
Ensure samples are Representativeness and adequately specified
PPQ Acceptance Criteria

§ A minimum of 3 consecutive batches meeting specifications for all

critical quality attributes and critical process parameters meeting
acceptance criteria.
§ Assessment of any non-critical process parameters and in-
process controls that fail to meet the pre-established parameters
ranges, with confirmation of no impact to the performance of the
unit operation or the validity of the qualification.
§ Description of any validation protocol exceptions, with
confirmation of no impact to the validity of the qualification.
PPQ documentation
Process Validation Protocol Contents:
• Objective
• Scope
• Background
• Validation strategy
• Supporting documents/ references
• Responsibilities
• Training requirements
• Manufacturing formula review
• Equipment and utility systems
• Training verifications
• Manufacturing process and control strategy
• Material sources and attributes
• Critical( and non-critical) quality attributes and process parameters
• Sampling plans and schedules
• Testing
• Acceptance criteria
• Deviations
PPQ documentation

Process Validation Report Contents

• Discuss and cross reference all aspects in the protocol
• Summarize data collected and analyze the data
• Evaluate any unexpected observation and additional data not specified
in the protocol
• Summarize all manufacturing non-conformities
• Describe in sufficient detail corrective actions or changes those can be
made
Set clear conclusion as whether data indicate the process met the
conditions, Overall process show sufficient control, and whether the
process is considered in a state of control and provide clear capability
statement based on statistical evaluation.
Stage #3;
Continued Process Verification (CPV)
• Assurance that process remains in a state of control
• Detection of undesired process variability
• Analyze process data related to product quality to establish acceptance
criteria

Allow timely detection of process drift & Ongoing feedback about

product performance and process maintenance
Stage #3; CPV

• Assess Risk due to change in the process or

the measurement behaviour
Monitor Collect • Focus on monitoring plans
• What type of data collected?
• How often reviewed?
• How does the process respond to change?
Assess
• Is there identified process trends?

Timely assessment - Do not wait large pool of data

Stage #3A ; Output

Short term
It shows evidence that process is:
• Capable Acceptance
limits
Internal limits for
trending

• Stable
• Consistent
• Remain Controlled

Preliminary limits are established as alert triggers based on PPQ data

Reviewed parameters and update risks
Enhanced Control strategy (monitoring data, frequency, process
response to change and identified trends)
Stage #3A; Enhanced sampling and monitoring
• Recommended continued monitoring and sampling of CPPs and
CQAs at the level established during PPQ stage
• Continue till no residual knowledge gap which means:
• Data available is sufficient to estimate significant variability
• Strong statement of control, reproducibility and capability is made
• Interpret signals or shifts – don’t rely only on them

Justification to reduce testing shall be made before

Stage#3B for routine monitoring.
Stage #3B; Routine CPV

Long-term
• Introduce Statistical Process Control (SPC) with rules for alerts
• Understand variations and trends
• Avoid limits updates that masks drift or special cause variation, track
limit history in case reset needed
• Statistical signals are yellow flags and should trigger response.
• Identify opportunities to continuously improve process

Continuous improvement
 CPV Plan; Considerations

What
CPV Plan shall include:
§ Product history and knowledge
§ Risk based (focus attention on areas of greatest risk) How CPV When

§ Frequency of production
§ May be possible to aggregate some data sources WHO

§ Not required to include every CQA, CPP & CMA in the CPV plan , but provide
justification for what is included/ not included ( why included items sufficient to
meet CPV plan’s objectives)
§ Addresses long-term variability (can not all be captured during development cycle)
§ Monitor process changes
§ Plan for periodic revision and reporting
Control Strategy and CPV Plan Revisions
Incident Investigate
based on risk Control Strategy
OOT
level Risk Revision
Change Risk level 1,2,3

Parameter No
included in
CS?
Yes
No CS need Yes Control Strategy
CPV Plan Review adjustment
Revision
?

No Add to CPV Yes

plan?
No Change in CPV Implement CPV Plan
Plan change
Statistical Process Control
Used in different stages for :
• Experimental design
• Sampling plans
• Variation reduction
• Process capability analysis and
• Process improvement plans
Understand fundamentals;
• Types of data; discrete and variable
• Sample vs population
• Basic descriptive statistics ; mean, standard deviation,
range , median , mode, etc.
• Statistical interval, acceptance sampling and control charts
Get inferences about untested product …
PV Challenges

• Process
Insufficient • PV guidance
knowledge •
•
Statistics
Cross functional

Insufficient • Limited number of commercial batches

data • Organizational silos

© 2022 WHO LPA

PV for legacy products
Legacy products characteristics: GAP /Risk assessment
• Previously validated. for product quality data
• Currently marketed.
• Typically in a stage of ongoing process verification.
• Pharmaceutical quality management system (PQMS) is Stage #3
in place.
PV strategy
• Evaluate product risk (product attributes, patient risk)
• Evaluate gaps (alignment with PQMS expectations)
• Evaluate product history (available data, quality history, Process
manufacturing experience,..etc) remediation/Improvement
• Stage 3, stage 1 , stage 2
• Prioritize products requiring remediations
• Output of all activities should be formally documented Stage #1&2
PV and Technology Transfer

• Facility fit assessment

• Resources and responsibilities
• Documentation
• Process samples
• Logistical considerations for international transfer
Example Product Transfer
CPV Vs APQR

Continuous Process verification (CPV) and Annual Product Quality Reviews

(APQR)Have similar Objectives of both maintaining the state of control and
identifying continuous improvement initiatives.
CPV:
• Allow reaching trends and identifying signals in a real time
• Maximally efficient, agile, flexible pharmaceutical manufacturing that
produces reliable high-quality product
• Focus more on CPPs and CMAs
APQR;
• High level summary of product performance
• Performed annually.

They complement each other and preferred to be integrated.

 Types of Process Validation

Type 1: Prospective Validation

• Product will be manufactured with a new formula or within a new facility.
• Premarket validation,
• Carried out before commencing routine production.
• Foundational type of validation because it is the starting point for any product that will be
released under new conditions.

Type 2: Retrospective Validation

• Conducted only when the manufacturing process has not formally undergone a documented
validation.
• Normally fulfilled with the use of historical data and trends analysis to provide evidence that
the process is at a state that it is intended to be in.
• It is no longer an acceptable approach to process validation because any product should
have already been validated before its commercial distribution.
Types of Process Validation

Type 3: Concurrent Validation

• Conducted during regular pharmaceutical production to demonstrate that the
process performs at the level that it should in the course of its actual execution.
• Acceptable approach to process validation under certain circumstances.
• Should only be used rarely.

Type 4: Revalidation
• Not widely used for drug products.
• Executed when prospective validation reaches a conclusion that the manufacturing
process is unable to produce the product consistently. Criteria for revalidation
indicated in the original validation protocol.
• May not be as comprehensive as the initial validation
Control Strategy in CTD Dossier

• Clear presentation of control strategy and its development is

essential to realize the added value of enhanced knowledge in
the marketing authorization.
• Control commitments are spread across the dossier; no
dedicated section to control strategy
• For Drug Substance (DS), S.2 is suitable for summary of DS
control strategy elements
• For Drug Product (DP), P.2 is suitable for summary of DP
control strategy elements
Message we wanted to convey

Data, Science and risk drives decisions Fit for the purpose is better
than trying to do everything

Innovation and continuous

Repetitious testing or inspecting improvement benefit from
does not change the result
harmonized knowledge and standards